Vascular smooth muscle (herein referred to as “VSM”) in the normal state is covered by an endothelial layer of cells as indicated in FIG. 1. In the normal state, VSM contracts in response to vasoconstrictor agonists, including norepinephrine. Lamb and Barna, 275 Am J Physiol H151 (1998). Disruption of the endothelial layer has been shown to increase sensitivity to these agonists. These findings are consistent with studies which showed that changes in the basal production of nitric oxide alters VSM responsiveness to vasoconstrictors. Joulow-Schaeffer et al., 259 Am J Physiol R38 (1990); Rees et al., 86 Proc Natl Acad Sci USA 3375 (1989); Wiklund et al., 185 Eur J Pharmacol 123 (1990).
Chloride ion channels are present in VSM (Klockner 424 Pflugers Arch 231 (1991); Lamb et al., 75 Circ Res 742 (1994)) and have been shown to be activated by vasoconstrictor agonists (Klockner and Isenberg, 418 Pflugers Arch 168 1991); Pacaud et al., 97 Br J Pharmacol 139 (1989)). Chloride ion currents have also been shown to contribute functionally to norepinephrine-induced contraction of normal vasculature. Lamb and Barna, 275 Am J Physiol H151 (1998). In that study, tamoxifen was shown to have no effect on the norepinephrine-induced contraction of normal vasculature (vasculature with intact endothelium). In Lamb and Barna, 275 Am J Physiol H161 (1998), the endothelium was shown to modulate the contribution of the chloride currents to norepinephrine-induced VSM constriction. The effects of tamoxifen on endothelium-compromised tissue was not studied, since no effect was seen in normal tissues. In other studies, a particular chloride ion channel, “CLC3”, was shown to be responsible for swelling-induced chloride conductance. Duan et al., 390 Nature 417 (1997). Tamoxifen was shown to block the ion channel responsible for swelling-induced chloride conductance, a result which had previously been demonstrated. Nilius et al., 428 Pflugers Arch 364 (1994).
The effects of tamoxifen on estrogen levels, and concomitant effects on other systems, including NE and dopamine expression, have also been studied. Kocsis et al., Vol. 69, Br J Exp Path 157 (1988); Etgen and Petitti, 49(6) J Neurochem 1732 (1987); Baksi et al., 20 Neuropharm 1163 (1981). Moreover, a method for treating peripheral vasoconstriction with tamoxifen citrate has been disclosed in U.S. Pat. No. 5,470,883. In that patent, the anti-estrogen effects of tamoxifen were said to be responsible for reducing the peripheral vasoconstriction of exogenously-administered adrenergic compound.
Vascular smooth muscle can be damaged by mechanical or physiological means. Medical procedures, such as balloon angioplasty, disease-induced or genetically-influenced pathogies, such as diabetes and hypertension, create risk or predisposal for endothelial damage. In addition, endothelial damage in itself may exacerbate these pathologic processes and contribute to symptoms which are associated with them. For instance, coronary artery disease results in localized endothelial damage, and sudden surges in natural vasoconstrictors (such as NE) can cause heart failure. Previous treatments for these endothelially-compromised patients have been limited to chemicals agents which cause system-wide VSM relaxation, and consequently, frequently cause side effects such as orthostasis (dizziness) due to transient low blood pressure during certain activities.